The third component of complement (C3) plays a central role in generating the biologically significant effects of the complement system. Not only does activation of C3 create cleavage products (e.g. C3a and C3b) which directly mediate defensive and inflammatory activities, but the larger cleavage prouct, C3b, forms part of the enzymes which activate C5-C9. Thus, C3 is also important in the generation of activities mediated by C5-C9. The identification of animals and humans with genetically determined deficiencies of individual components of complement has been valuable in generating knowledge about the genetics, biochemistry and biological significance of the complement system. Although a few humans with genetically determined C3 deficiency have been described, until recently no experimental animals with C3 deficiency had been identified. In 1981 we described a colony of dogs with a genetically determined total deficiency of C3. the following specific aims are uniquely suited to study in the C3-deficient dog and should provide important insight into selected aspects of the role of C3 in immunobiology: 1) We will characterize the renal disease in C3-deficient dogs in order to gain insight into the etiology and pathogenesis of the renal disease found in human patients with both inherited and acquired abnormalities in the complement system. 2) We will study the clearance of soluble immune complexes in C3 deficient dogs in order to gain insight into the role of C3 in the processing of immune complexes in vivo. 3) We will determine if C3-deficient dogs have normal antibody formation in order to clarify the role of C3 in antibody formation in vivo. 4) We will investigate the molecular basis for the C3 deficiency in C3-deficient dogs in order to gain insight into one possible molecular mechanisms for genetically determined C3 deficiency.